The long-term objective of the proposed study is to elucidate the mechanisms of variation in influenza A and B viruses. This includes both antigenic variation and variation in the other six gene products of influenza viruses. The objectives and methods are: 1) To prepare monoclonal antibodies to each of the gene products of the reference strains of H1N1, H3N2, and influenza B viruses. 2) To utilize monoclonal antibodies to determine the number and location of the antigenic determinants on the hemagglutinin and neuraminidase molecules of these viruses and to relate them to the primary structure of the molecules. The number of determinants will be established with monoclonal antibodies in serological assays. Antigenic variants will be selected, the surface proteins will be peptide mapped and variant peptides related to the primary amino acid sequence. The location of the antigenic determinants on the molecules will be determined by X-ray crystalography. 3) To characterize the gene product of influenza viruses with monoclonal antibodies and determine what constitutes an epidemiologically important strain using serological assays and RNA hybridization. 4) To establish the gene constellations of avian and mammalian influenza viruses that control tissue tropism and host range using recombinants between avian strains of influenza virus that replicate in the cells lining the intestinal tract of ducks and humans strain that do not replicate in ducks. 5) To elucidate the role of the different determinants on the gene products of influenza virus in antibody- and cell-mediated immunity using monoclonal antibodies in in vivo and in vitro assays.